RU2017115315A - ANTIBODIES TO A GLUCCORTICOID-INDUCED TUMOR NECROSIS FACTOR (GITR) RECEPTOR AND METHODS OF APPLICATION - Google Patents

ANTIBODIES TO A GLUCCORTICOID-INDUCED TUMOR NECROSIS FACTOR (GITR) RECEPTOR AND METHODS OF APPLICATION Download PDF

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RU2017115315A
RU2017115315A RU2017115315A RU2017115315A RU2017115315A RU 2017115315 A RU2017115315 A RU 2017115315A RU 2017115315 A RU2017115315 A RU 2017115315A RU 2017115315 A RU2017115315 A RU 2017115315A RU 2017115315 A RU2017115315 A RU 2017115315A
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seq
amino acid
acid sequence
antibody
variable
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RU2017115315A
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RU2017115315A3 (en
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Уэйн А. МАРАСКО
Дэ-Куань ЧАН
Чэнь СЮЙ
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Дана-Фарбер Кэнсер Инститьют, Инк.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Claims (50)

1. Изолированное гуманизированное моноклональное антитело или его антигенсвязывающий фрагмент, которые связываются с человеческим рецептором глюкокортикоид-индуцированного фактора некроза опухоли (GITR), содержащие:1. An isolated humanized monoclonal antibody or antigen binding fragment thereof that binds to the human receptor for a glucocorticoid-induced tumor necrosis factor (GITR), comprising: a. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 2, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 4;a. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 2, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 4; b. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 6, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 8;b. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 6, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 8; c. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 10, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 12;c. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 10, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 12; d. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 14, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 16;d. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 14, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 16; e. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 18, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 20;e. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 18, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 20; f. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 22, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 24;f. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 22, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 24; g. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 26, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 28;g. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 26, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 28; h. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 30, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 32;h. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 30, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 32; i. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 34, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 36;i. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 34, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 36; g. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 38, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 40; илиg. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 38, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 40; or k. вариабельную область тяжелой цепи, содержащую аминокислотную последовательность SEQ ID NO: 42, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 44.k. the variable region of the heavy chain containing the amino acid sequence of SEQ ID NO: 42, and the variable region of the light chain containing the amino acid sequence of SEQ ID NO: 44. 2. Изолированное гуманизированное моноклональное антитело или его антигенсвязывающий фрагмент, где антитело или антигенсвязывающий фрагмент содержит:2. An isolated humanized monoclonal antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment comprises: (a) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 45, 46 или 47, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 48, 49 или 50;(a) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 45, 46 or 47, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 48, 49 or 50; (b) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 51, 52 или 53, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 54, 55 или 56;(b) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 51, 52 or 53, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 54, 55 or 56; (c) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 57, 58 или 59, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 60, 61 или 62;(c) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 57, 58 or 59, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 60, 61 or 62; (d) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 63, 64 или 65, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 66, 67 или 68;(d) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 63, 64 or 65, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 66, 67 or 68; (e) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 69, 70 или 71, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 72, 73 или 74;(e) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 69, 70 or 71, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 72, 73 or 74; (f) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 75, 76 или 77, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 78, 79 или 80;(f) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 75, 76 or 77, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 78, 79 or 80; (g) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 81, 82 или 83, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 84, 85 или 86;(g) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 81, 82 or 83, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 84, 85 or 86; (h) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 87, 88 или 89, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 90, 91 или 92;(h) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 87, 88 or 89, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 90, 91 or 92; (i) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 93, 94 или 95, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 96, 97 или 98;(i) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 93, 94 or 95, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 96, 97 or 98; (g) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 99, 100 или 101, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 102, 103 или 104; или(g) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 99, 100 or 101, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 102, 103 or 104; or (k) вариабельную определяющую комплементарность область тяжелой цепи 1, 2 или 3 (VH-CDR), содержащую аминокислотные последовательности SEQ ID NO. 105, 106 или 107, соответственно; и вариабельную определяющую комплементарность область легкой цепи 1, 2 или 3 (VL-CDR), содержащую аминокислотные последовательности SEQ ID NO. 108, 109 или 110,(k) a variable complementarity determining region of the heavy chain 1, 2 or 3 (VH-CDR) containing the amino acid sequence of SEQ ID NO. 105, 106 or 107, respectively; and a variable complementarity determining region of the light chain 1, 2 or 3 (VL-CDR) containing the amino acid sequences of SEQ ID NO. 108, 109 or 110, где указанные антитело или антителосвязывающий фрагмент связываются с человеческим рецептором глюкокортикоид-индуцированного фактора некроза опухоли (GITR).wherein said antibody or antibody binding fragment binds to a human receptor for a glucocorticoid-induced tumor necrosis factor (GITR). 3. Антитело по п. 1, где указанное антитело является моновалентным или бивалентным.3. The antibody of claim 1, wherein said antibody is monovalent or bivalent. 4. Антитело по п. 1, где указанное антитело представляет собой одноцепочечное антитело.4. The antibody of claim 1, wherein said antibody is a single chain antibody. 5. Антитело по п. 1, где указанное антитело имеет аффинность связывания в интервале от 10-5 M до 10-12 M.5. The antibody according to claim 1, where the specified antibody has a binding affinity in the range from 10 -5 M to 10 -12 M. 6. Антитело по п. 1, где указанное антитело имеет константную область тяжелой цепи IgG4.6. The antibody of claim 1, wherein said antibody has an IgG4 heavy chain constant region. 7. Антитело по п. 1, где Fc область содержит мутации по положениям аминокислот 234 и 235.7. The antibody of claim 1, wherein the Fc region contains mutations at amino acid positions 234 and 235. 8. Антитело по п. 7, где мутациями являются L234A и L235A.8. The antibody of claim 7, wherein the mutations are L234A and L235A. 9. Антитело по п. 1, где указанное антитело представляет собой биспецифическое антитело, которое также связывается с опухолеассоциированным антигеном, цитокином или рецептором клеточной поверхности.9. The antibody of claim 1, wherein said antibody is a bispecific antibody that also binds to a tumor-associated antigen, cytokine, or cell surface receptor. 10. Антитело по любому одному из предшествующих пунктов, связанное с терапевтическим средством.10. The antibody according to any one of the preceding paragraphs, associated with a therapeutic agent. 11. Антитело по п. 10, где указанное терапевтическое средство представляет собой токсин, радиоактивную метку, миРНК, малую молекулу или цитокин.11. The antibody of claim 10, wherein said therapeutic agent is a toxin, radioactive label, siRNA, small molecule, or cytokine. 12. Клетка, продуцирующее антитело по любому одному из пп. 1-11.12. A cell producing an antibody according to any one of paragraphs. 1-11. 13. Способ истощения регуляторных Т-клеток у субъекта, включающий в себя введение нуждающемуся субъекту композиции, содержащей антитело по любому одному из пп. 1-11.13. A method of depleting regulatory T cells in a subject, comprising administering to a needy subject a composition comprising an antibody according to any one of claims. 1-11. 14. Способ усиления иммунного ответа на антиген, включающий в себя введение нуждающемуся субъекту композиции, содержащей антитело по любому одному из пп. 1-11.14. A method of enhancing an immune response to an antigen, comprising administering to a needy subject a composition comprising an antibody according to any one of claims. 1-11. 15. Способ по п. 14, где указанный антиген представляет собой вирусный антиген, бактериальный антиген или опухолеассоциированный антиген.15. The method of claim 14, wherein said antigen is a viral antigen, a bacterial antigen, or a tumor associated antigen. 16. Способ по п. 14, где указанное введение указанного антитела вызывает увеличение антигенспецифичной активности Т-клеток.16. The method of claim 14, wherein said administration of said antibody causes an increase in antigen-specific activity of T cells. 17. Способ по п. 14, где указанное введение указанного антитела вызывает увеличение цитотоксичности NK-клеток.17. The method of claim 14, wherein said administration of said antibody causes an increase in cytotoxicity of NK cells. 18. Способ по п. 14, дополнительно включающий в себя введение указанному субъекту IL-15.18. The method of claim 14, further comprising administering to said subject IL-15. 19. Способ лечения или снятия симптома злокачественного новообразования, включающий в себя введение нуждающемуся субъекту композиции, содержащей антитело по любому одному из пп. 1-11.19. A method of treating or relieving a symptom of a malignant neoplasm, comprising administering to a needy subject a composition comprising an antibody according to any one of claims. 1-11. 20. Способ по п. 19, где указанное злокачественное новообразование является злокачественным новообразованием, в котором GITR или его лиганд, GITR-L, сверхэкспрессируется.20. The method according to p. 19, where the specified malignant neoplasm is a malignant neoplasm in which GITR or its ligand, GITR-L, overexpressed. 21. Способ по п. 20, включающий в себя дополнительное введение указанному субъекту цитокина или химиотерапевтического средства.21. The method of claim 20, further comprising administering to the subject a cytokine or chemotherapeutic agent. 22. Способ по п. 21, где цитокин представляет собой IL-15.22. The method of claim 21, wherein the cytokine is IL-15. 23. Нуклеиновая кислота, содержащая последовательность нуклеиновой кислоты с SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43.23. A nucleic acid comprising a nucleic acid sequence with SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43. 24. Нуклеиновая кислота, кодирующая полипептид с SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44.24. A nucleic acid encoding a polypeptide with SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44. 25. Полипептид, содержащий аминокислотную последовательность SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44.25. The polypeptide containing the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40 , 42, 44. 26. Вектор, содержащий нуклеиновую кислоту п. 23 или 24.26. A vector containing the nucleic acid of claim 23 or 24. 27. Клетка, содержащая вектор по п. 26.27. A cell containing the vector of claim 26.
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